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Background: Ex situ donor liver machine perfusion is a promising tool to assess organ viability prior to transplantation and platform to investigate novel therapeutic interventions. However, the wide variability in donor and graft characteristics between individual donor livers limits the comparability of results. We investigated the hypothesis that the development of a split liver ex situ machine perfusion protocol provides the ideal comparative controls in the investigation of machine perfusion techniques and therapeutic interventions, thus leading to more comparable results. Methods: Four discarded human donor livers were surgically split following identification and separation of right and left inflow and outflow vessels. Each lobe, on separate perfusion machines, was subjected to normothermic perfusion using an artificial hemoglobin-based oxygen carrier solution for 6 h. Metabolic parameters as well as hepatic artery and portal vein perfusion parameters monitored. Results: Trends in hepatic artery and portal vein flows showed a general increase in both lobes throughout each perfusion experiment, even when normalized for tissue weight. Progressive decreases in perfusate lactate and glucose levels exhibited comparable trends in between lobes. Conclusion: Our results demonstrate comparability between right and left lobes when simultaneously subjected to normothermic machine perfusion. In the pre-clinical setting, this model provides the ideal comparative controls in the investigation of therapeutic interventions., Competing Interests: JA is a clinical research fellow at the Queen Elizabeth Hospital in Birmingham and employed by University Hospitals Birmingham. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Attard, Osei-Bordom, Boteon, Wallace, Ronca, Reynolds, Perera, Oo, Mergental, Mirza and Afford.)

Tumour recurrence is currently a hot topic in liver transplantation. The basic mechanisms are increasingly discussed, and, for example, recurrence of hepatocellular carcinoma is often described in pre-injured donor livers, which frequently suffer from significant ischemia/reperfusion injury. This review article highlights the underlying mechanisms and describes the specific tissue milieu required to promote tumour recurrence after liver transplantation. We summarise the current literature in this field and show risk factors that contribute to a pro-tumour-recurrent environment. Finally, the potential role of new machine perfusion technology is discussed, including the most recent data, which demonstrate a protective effect of hypothermic oxygenated perfusion before liver transplantation.

Ischemia/reperfusion injury (IRI) is the main cause of complications following liver transplantation. Reactive oxygen species (ROS) were thought to be the main regulators of IRI. However, recent studies demonstrate that ROS activate the cytoprotective mechanism of autophagy promoting cell survival. Liver IRI initially damages the liver endothelial cells (LEC), but whether ROS-autophagy promotes cell survival in LEC during IRI is not known. Primary human LEC were isolated from human liver tissue and exposed to an in vitro model of IRI to assess the role of autophagy in LEC. The role of autophagy during liver IRI in vivo was assessed using a murine model of partial liver IRI. During IRI, ROS specifically activate autophagy-related protein (ATG) 7 promoting autophagic flux and the formation of LC3B-positive puncta around mitochondria in primary human LEC. Inhibition of ROS reduces autophagic flux in LEC during IRI inducing necrosis. In addition, small interfering RNA knockdown of ATG7 sensitized LEC to necrosis during IRI. In vivo murine livers in uninjured liver lobes demonstrate autophagy within LEC that is reduced following IRI with concomitant reduction in autophagic flux and increased cell death. In conclusion, these findings demonstrate that during liver IRI ROS-dependent autophagy promotes the survival of LEC, and therapeutic targeting of this signaling pathway may reduce liver IRI following transplantation., (© 2018 by the American Association for the Study of Liver Diseases.)

Background: Normothermic machine perfusion of the liver (NMP-L) is a novel technique that preserves liver grafts under near-physiological conditions while maintaining their normal metabolic activity. This process requires an adequate oxygen supply, typically delivered by packed red blood cells (RBC). We present the first experience using an acellular hemoglobin-based oxygen carrier (HBOC) Hemopure in a human model of NMP-L., Methods: Five discarded high-risk human livers were perfused with HBOC-based perfusion fluid and matched to 5 RBC-perfused livers. Perfusion parameters, oxygen extraction, metabolic activity, and histological features were compared during 6 hours of NMP-L. The cytotoxicity of Hemopure was also tested on human hepatic primary cell line cultures using an in vitro model of ischemia reperfusion injury., Results: The vascular flow parameters and the perfusate lactate clearance were similar in both groups. The HBOC-perfused livers extracted more oxygen than those perfused with RBCs (O2 extraction ratio 13.75 vs 9.43 % ×10 per gram of tissue, P = 0.001). In vitro exposure to Hemopure did not alter intracellular levels of reactive oxygen species, and there was no increase in apoptosis or necrosis observed in any of the tested cell lines. Histological findings were comparable between groups. There was no evidence of histological damage caused by Hemopure., Conclusions: Hemopure can be used as an alternative oxygen carrier to packed red cells in NMP-L perfusion fluid.

Background: Liver transplantation is the criterion standard treatment for hepatocellular carcinoma, but tumor recurrence remains a problem leading to a worse prognosis. We aimed to evaluate factors associated with recurrence of hepatocellular carcinoma and survival after this procedure., Methods: We retrospectively reviewed data from 101 patients submitted to liver transplantation because of hepatocellular carcinoma from January 2005 to January 2012 at our single center. Univariate and multivariate analyses were performed to identify preoperative factors and histologic findings associated with lower survival rates and recurrence. The significance level was 5%., Results: There was recurrence in 10 cases (9.9%), with an average time of 25.28 ± 26.92 months. Microvascular invasion (P = .005; hazard ratio [HR], 4.94; 95% confidence interval [CI], 1.42-17.12) was an independent factor for recurrence. Microvascular invasion (P = .035; HR, 1.87; 95% CI, 1.04-3.25) and tumors outside the criteria of the University of San Francisco (P = .046; HR, 1.81; 95% CI, 1.01-3.25) were independent factors for the risk of death. Poorly differentiated tumors had a higher level of alphafetoprotein (P = .03), and values <100 ng/mL were associated with well differentiated tumors., Conclusions: Microvascular invasion was associated with recurrence and lower survival. Tumors outside the criteria of the University of California, San Francisco had lower survival. Alpha-fetoprotein levels >100 ng/mL were associated with poorly differentiated tumors., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: A liver transplantation is the first choice of treatment for patients with hepatic insufficiency due to chronic diseases. Infections in the postoperative period represent one of the main causes of mortality in these cases. However, few articles have evaluated the predominance of certain infectious diseases and their influence on postoperative mortality., Methods: We retrospectively evaluated the medical records of 236 patients who underwent liver transplantation from January 1997 to January 2007. In these records we checked the serological profiles for these diseases: toxoplasmosis, syphilis, human T lymphotropic virus (HTLV) I and II infection, Chagas disease, hepatitis A, hepatitis B, hepatitis C, paracoccidioidomycosis, tuberculosis, acquired immunodeficiency syndrome, cytomegalovirus (CMV), and mononucleosis (Epstein-Barr virus [EBV]). The statistical analysis was performed by table frequencies., Results: CMV showed positivity (CMV-IgG) in 94.7% of patients, 95.8% for EBV, 33.3% for toxoplasmosis, 47.9% for hepatitis C, and 5% for hepatitis B., Conclusion: Our analysis showed the importance of serological investigations and diagnostic examinations before the transplantation procedure, seeking to minimize possible reactivation of the disease after the use of immunosuppression drugs, particularly in the first 6 months after transplantation, or even to avoid a primary infection., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)